The present invention relates to a method of use of polyether ionophores as antiobesity and hypotriglyceridemic agents.
Obesity represents a state of increased body fat which may decrease longevity, aggravate the onset and progression of other diseases, e.g., heart disease, diabetes, gall stones, for example, and impact on one's social or economic status. [The Obese Patient, G. A. Bray, Vol. IX in the series "Major Problems in Internal Medicine", W. B. Saunders Co., 1976].
Plasma triglycerides are risk factors for ischemic heart disease, e.g. atherosclerosis. [The Heritable Hypolipoproteinemias and Atherosclerosis, C. J. Glueck and R. W. Fallat, Lipids, Lipoproteins and Drugs, pp 169-183 and 305-316, Plenum Press, 1975].
Thus an agent which exhibits activity in the reduction of obesity and the lowering of triglyceride levels would have a significant positive effect on heart disease, diabetes, gall stones, for example, through preventative measures.
Polyether ionophores are compounds which facilitate the transport of monovalent or divalent cations across a membrane. The "polyether" nature of the ionophore refers to the considerable number of tetrahydro-pyrans and -furans found in the ionophore structure. For the most part, these compounds have been found to exhibit weak antibiotic activity. Other utilities for many of these compounds include activities as growth promotants (U.S. Pat. No. 3,839,557), coccidiostatic agents (U.S. Pat. Nos. 3,719,753 and 3,577,531) and cardiovascular agents (U.S. Pat. No. 3,873,715).
The following compilation represents typical polyether compounds which exhibit an ionophoric effect and are useful in treating obesity and high triglyceride levels. The formulas which follow utilize the shorthand notations Me and Et which represent methyl and ethyl, respectively.
Nigericin ##STR1## PA1 Antibiotic X-206 ##STR3## PA1 Salinomycin ##STR4## PA1 Grisorixin ##STR5## PA1 Laidlomycin ##STR6## R.sub.1 .dbd.CH(Me)CO.sub.2 H,R.sub.2 =Me PA1 Dianemycin ##STR7## PA1 Lenoremycin (Antibiotic A-130A) ##STR8## PA1 Factor A (R.sub.1 .dbd.R.sub.2 .dbd.Me, R.sub.3 .dbd.OH PA1 Factor B (R.sub.1, R.sub.2 .dbd.Me; R.sub.3 .dbd.O PA1 Factor D (R.sub.1, R.sub.2 .dbd.Me, Et; R.sub.3 .dbd.OH) ##STR9## PA1 Lonomycin A PA1 (TM-481) ##STR10## PA1 Alborixin ##STR11## PA1 Septamycin ##STR12## PA1 Antibiotic A-204A ##STR13## PA1 Antibiotic 38295 ##STR14## PA1 Iso-Lasalocid A ##STR16## PA1 Lysocellin ##STR17## PA1 Mutalomycin ##STR18## PA1 Noboritomycin A and B ##STR19## PA1 Antibiotic A23187 (Calcimycin) ##STR20## PA1 Antibiotic X-14547A ##STR21## PA1 Carriomycin (T-42082) ##STR22## PA1 K-41 (A-32887) ##STR23## PA1 CP44161 ##STR24## PA1 BL-580 .DELTA. ##STR25## PA1 Ionomycin PA1 CP 38,986 PA1 30,504RP
Nigericin has been known for some time under the names helixin C, antibiotic X-464, antibiotic K-178, polyetherin A, and azalomycin M. Its structure was characterized by Steinrauf et al., Biochemical and Biophysical Research Communications 33, 29 (1968). Harnes et al., Antibiotic and Chemotherapy I, 594-96 (1951) originally mentioned nigericin. It was also described by Gorman et al. in U.S. Pat. No. 3,555,510.
The organism which produces nigericin is a strain of Streptomyces violaceoniger which is on unrestricted deposit under identification number NRRL B1356 in the Northern Research and Utilization Development Division, Agricultural Research Service, U.S. Dept. of Agriculture, Peoria, Ill. The preparation of nigericin is described in U.S. Pat. Nos. 3,794,732 and 3,839,557.
Monensin R.sub.1 =CH(Me)CO.sub.2 H,R.sub.2 =Me,R.sub.3 =Et PA0 Factor B R.sub.1 =CH(Me)CO.sub.2 H,R.sub.2,R.sub.3 =Me PA0 Factor C R.sub.1 =(CH.sub.2).sub.3 CO.sub.2 H,R.sub.2 =Me,Me PA0 Factor D R.sub.1 =CH(Me)CO.sub.2 H,R.sub.2 =Et,R.sub.3 =Me ##STR2## PA0 A 28086 PA0 Homolog C R.sub.2 .dbd.Et,R.sub.1 .dbd.R.sub.3 .dbd.R.sub.4 .dbd.Me PA0 Homolog D R.sub.3 .dbd.Et,R.sub.1 .dbd.R.sub.2 .dbd.R.sub.4 .dbd.Me PA0 Homolog E R.sub.4 .dbd.Et,R.sub.1 .dbd.R.sub.2 .dbd.R.sub.3 .dbd.Me
Monensin was described by Haney et al., U.S. Pat. No. 3,501,568. The substance commonly known as monensin or A 3823 complex is actually a mixture of four components. These four components are included in the term "monensin" as used herein.
Monensin is the fermentation product of an organism which can be found on unrestricted deposit under the number ATCC 15413 in the American Type Culture Collection, Rockville, Md. A method of production for the monensin complex is disclosed in U.S. Pat. No. 3,501,568.
Also within the ambit of the present invention are the metabolites of monensin such as A-27106 disclosed and claimed in U.S. Pat. No. 3,932,619. A-27106 is produced from the conversion of monensin by an enzyme system produced by an organism Streptomyces candidus available as accession number NRRL 5449 at Northern Regional Research Laboratories, Peoria, Ill.
The compound X-206 was reported for the first time in 1951 by Berger et al., JACS 73, 5295-98 (1951). The Streptomyces organism from which one is able to obtain antibiotic X-206 is available at Center International d'Information sur Les Antibiotiques (International Center for Information on Antibiotics) Liege, Belgium, which lists the organism on page 31 of its Bulletin No. 3 (1966). Its formula has been characterized by Blount et al., Chemical Communications (London), p. 533, 1975. A method for the preparation of X-206 is disclosed in U.S. Pat. Nos. 3,794,732 and 3,839,557.
The compound Salinomycin was first reported in 1973 by Kinahsi et al., Tetrahedron Letters, 49, 4955 (1973). Salinomycin is the fermentation product of an organism (Streptomyces albus) which can be found on unrestricted deposit under Number ATCC 21838 in the American Type Culture Collection, Rockville, Md. and from the Fermentation Research Institute in Japan as Streptomyces albus 80, 614 (No. 419). A method of producing Salinomycin by fermentation is disclosed by Tanaka et al. in U.S. Pat. No. 3,857,948. Related compounds to salinomycin have also been reported in the literature, for example, Deoxy-(0-8)-salinomycin by Shibata et al., Japanese Pat. No. 51-8619; Salinomycin II by Yonehara et al., Japanese Pat. No. 50-132190; and the C-17 epimer of deoxy-(0-8)-salinomycin by Westley et al., Journal of Antibiotics, 30, 610 (1977).
The compound Grisorixin was first reported in 1970 by Gachon et al., Chem. Commun., P 1421 (1970). The compound was found to differ by only a single oxygen atom from nigericin. The Streptomyces organism from which one is able to obtain the compound Grisorixin is Streptomyces griseus. A method for the preparation of Grisorixin is shown in the Gachon et al. article.
The compound "laidlomycin" and a method for its production has been disclosed by Kitame et al. in the Journal of Antibiotics, Vol. XXVII No. 11, pp. 884-888, 1974. The compound is produced by the fermentation of a Streptomyces eurocidicus var. asterocidius (similar) assigned the designation Streptomyces S-822. This species is indexed as S-822 at the Department of Bacteriology, Tohoku University School of Medicine, Sendai, Japan.
The compound Dianemycin was first reported in 1971 by Czerwinski et al., Biochem. Biophys. Res. Commun., 45, 1284 (1971). Dianemycin is the fermentation product of an organism (Streptomyces hygroscopicus) which can be found on unrestricted deposit under number NRRL 3444 in the Northern Research and Utilization Development Division, Agricultural Research Service, U.S. Dept. of Agriculture, Peoria, Ill. A method for its preparation is disclosed in U.S. Pat. No. 3,577,531 to Gorman et al.
The compound A-130A was discovered by Oikawa et al. and is disclosed together with a method for its production in U.S. Pat. No. 3,903,264 issued Sept. 2, 1975. The compound is produced by the fermentation of a strain of Streptomyces hygroscopicus available to the public under the accession number ATCC 21840 at the American Type Culture Collection in Rockville, Md.
Recently, Blount et al. in Chemical Comm. (London), pp. 853-855 (1975) have provided a structural elucidation of this compound.
Antibiotic complex A 28086 is made up of at least three components, one of which, factor A, is known as narasin. The complex is produced by fermentation of an organism, Streptomyces aureofociens which can be found on deposit in the Northern Regional Research Laboratories in Peoria, Ill. under NRRL numbers 8092 or 5758. A method of fermentation to produce the A 28086 complex is disclosed in Belgium Pat. No. 830,043 published Dec. 10, 1975.
The antibiotic lonomycin was first reported and elucidated structurally by Omura et al. in Journal of Antibiotics, Vol. XXIX, No. 1, pp. 15-20, Jan. 1976 and Otake et al., Tet. Letters No. 47, pp. 4147-4150, 1975. The antibiotic is produced by a Streptomyces ribosidificus strain TM-481 which is deposited as ATCC No. 31051 at the American Type Culture Collection in Rockville, Md. A method of producing the antibiotic by fermentation is disclosed by Sawada et al. in U.S. Pat. No. 3,950,514. Subsequent publications by Riche et al. (as Emericid) in Chem. Comm. (London), pp 951-952 (1975) and Benazet et al. (as 31599 RP) at the 9th International Congress of Chemotherapie in London, July 13-18, 1975 disclosed identical compounds to lonomycin. Lonomycins B and C have also been disclosed along with their structures by H. Seto et al., in Journal of Antibiotics, 31, 929 (1978b).
The compound Alborixin was first reported by M. Alleaume et al., Chem. Comm. (London), pp 411-412 (1975). The compound is obtained by the fermentation of a strain of Streptomyces albus sp. 3840 as reported by Delhomme et al. in Journal of Antibiotics, Vol. XXIX, No., 7, pp 692-695 (1976).
The compound Septamycin also known as A 28695 together with A 28695B was first described in U.S. Pat. No. 3,839,558 to Hamill et al. The structure was elucidated by T. J. Petcher et al., Chem. Comm., (London) 697 (1974). Septamycin differs from A-204A (below) in the loss of one of the five methoxyls present in A-204A and a change in the configuration and the point of attachment of the glycoside-like branched tetrahydropytonyl ring. Septamycin is obtained by the fermentation of a strain of Streptomyces hydroscopicus as disclosed in the above mentioned patent.
The compound A-204A was reported for the first time by N. D. Jones et al., J. Amer. Chem. Soc., 95, 3399 (1973). It is obtained by the fermentation of a strain of the organism Streptomyces albus. This strain is found on unrestricted deposit under the number NRRL 3384 in the Northern Research and Utilization Development Division, Agricultural Research Service, U.S. Dept. of Agriculture, Peoria, Ill. A method for the production of A-204A (I) is disclosed in U.S. Pat. No. 3,705,238. U.S. Pat. Nos. 3,953,474 and 3,907,832 also disclose information on the above antibiotic which is disclosed as a complex.
The compound antibiotic 38295 was first reported by Celmer et al., in Belgium Pat. No. 831,947 published on Feb. 2, 1976. The patent discloses a method of production for the antibiotic by fermentation of the organism Streptomyces hygroscopicus found on deposit under the number ATCC 31050 in the American Type Culture Collection, Rockville, Md. ##STR15## Lasalocid A R.sub.1 .dbd.R.sub.2 .dbd.R.sub.3 .dbd.R.sub.4 .dbd.Me Lasalocid B R.sub.1 .dbd.Et,R.sub.2 .dbd.R.sub.3 .dbd.R.sub.4 .dbd.Me
The compound Lasalocid A, its isomer and its homologs are produced by the fermentation of the organism Streptomyces lasaliensis. The organism can be found on unrestricted deposit under the number NRRL 3382 in the Northern Research and Utilization Development Division, Agricultural Research Service, U.S. Dept. of Agriculture, Peoria, Ill. and under the number ATCC 31180 in the American Type Culture Collection, Rockville, Md. The compound Lasalocid A, its isomer and its homologs have been first reported by Berger et al., J. Amer. Chem. Soc., 73, 5295 (1951), J. Westley et al., J. Antibiot., 27, 597 (1974) and J. Westley et al., J. Antibiot., 27, 744 (1974) respectively. Also disclosed in these articles are methods for the preparation of the respective compounds.
The compound Lysocellin was first reported by Ebata et al. in J. Antibiotic., 28, 118-121 (1975). The compound is produced by fermentation of a Streptomyces cocaoi var. asoensis K-9 Met. mutant. It has also been found this compound, also known as X-14537A, can be produced by fermentation of a Streptomyces longwoodensis which is deposited as ATCC 20251 at the American Type Culture Collection in Rockville, Md. and the fermentative method disclosed in Int. J. of Systematic Bacteriology, Vol. 26 (3), pp 310-322, 1976 article by Palleroni et al.
The compound Mutalomycin is described by Fehr et al. in the Journal of Antibiotics, 30, pp 903-907, 1977. The antibiotic is the product of the fermentation of the Streptomyces mutabilis deposited as NRRL 8088 at the Northern Regional Research Laboratories.
Noboritomycin A and B are disclosed as produced by the fermentation of the organism Streptomyces noboritoensis deposited as NRRL 8123 at the Northern Regional Research Laboratories, Peoria, Ill.
The compound A 23187 was first reported by M. O. Chaney et al., J. Amer. Chem. Soc., 96, 1932 (1974) as containing two cyclic ethers in a spiro ring system and a carboxylic acid function. The molecular formula was calculated as C.sub.29 H.sub.37 N.sub.3 O.sub.6. The compound is obtained by the fermentation of a strain of Streptomyces chartreusensis. A method of preparation of A 23187 by fermentation of the Streptomyces chartreusensis is set forth in U.S. Pat. No. 3,923,823 to Gale et al. The organism is on deposit at the Northern Regional Research Laboratories, Peoria, Ill. as NRRL 3882.
Antibiotic X-14547 is disclosed in U.S. Pat. No. 4,100,171 issued July 11, 1978 to Westley et al. The compound is obtained by fermentation of the organism Streptomyces antibioticus deposited as NRRL 8167 at the U.S. Department of Agriculture, Agricultural Research Service, Northern Regional Research Laboratories, Peoria, Ill. A structure for the compound is disclosed in the patent.
Carriomycin is disclosed in U.S. Pat. No. 4,069,316 to Imada et al. The compound is produced by the fermentation of the organism Streptomyces hydgroscopicus T-42082 deposited as ATCC 31080 at the American Type Culture Collection, Rockville, Md. I.R. and N.M.R. data for the antibiotic are disclosed.
The compound "K-41" and a method for its production has been disclosed by Tsuzi et al. in the Journal of Antibiotics, Vol. XXIX, No. 1, pp 10-14, 1976. The compound is produced by the fermentation of a Streptomyces hygroscopicus given the designation FERM-P 1324 and on deposit at the Fermentation Research Institute, agency of Industrial Science and Technology, Chiba, Japan. Further information can be found in J.C.S. Chem. Comm., 682-683 and 683-684(1978).
CP44,161 is disclosed in U.S. Pat. No. 4,081,532 issued Mar. 28, 1978 to Celmer et al. The compound is obtained by the fermentation of the organism Dactylosporangium aurantiacum deposited as ATCC 23491, and Dactylosporangium salmoneum deposited as 31222,31223 and 31224 at the American Type Culture Collection, Rockville, Maryland. IR spectra of the antibiotic is disclosed.
BL 580 .DELTA. is disclosed in Belgian Pat. No. 856,314 issued Dec. 30, 1977. The fermentation of the antibiotic is carried out by a strain of Streptomyces hygroscopicus deposited as NRRL 8180.